1. Field of the Invention
The present invention relates to a tumor selective and biodegradable polyphosphazene-platinum(II) conjugate antitumor agent and a preparation method thereof.
2. Description of the Prior Art
The platinum(II) antitumor agent such as cisplatin or carboplatin is one of the most widely used antitumor agents in the world. In particular, it has been is known that cisplatin shows superior antitumor activities against testicular cancer, ovarian cancer, bladder cancer, etc.
Cisplatin, which is the first-generation platinum group antitumor agent having a simple structure, is disadvantageous in that it has been restricted in use for cancer treatment due to its severe adverse effects on kidney, bone marrow and nervous system as well as its acquired resistence in long term use and low solubility in water, etc. (D. Lebwohl, R. Canetta, Eur. J. Cancer, 34, 1522 (1998)).
Accordingly, a great deal of researches for the development of new platinum complexes having lower toxicity and higher solubility in water, as well as being capable of overcoming drug-resistance, have been actively performed worldwide. As a result, carboplatin was developed as a second-generation platinum group antitumor agent and presently used in clinic (E. Wong, C. M. Giandomenico, Chem, Rev., 99, 2451 (1999)). In carboplatin, chloride anions were replaced with a dicarboxylate anion, thereby to improve solubility in water and to reduce toxicity.
However, in spite that toxicity has been reduced, carboplatin shows stronger adverse effect on bone marrow with lower and narrower spectrum of antitumor activity compared with cisplatin. Therefore, it has been used only for a patient of ovarian cancer or lung cancer having a kidney dysfunction. Therefore, development of a next generation antitumor agent having low toxicity, high solubility in water, high tumor selectivity and the like are urgently required.
In the meantime, since the discovery that polymers with appropriate molecular weights show preferentially enhanced permeability and retention in solid tumor tissues (L. W. Seymour, Y. Miyamoto, H. Maeda, M. Brereton, J. Strohalem, K. Ulbrich and R. Duncan, Eur. J. Cancer, 31A, 766 (1995).), a great deal of researches have been performed worldwide for development of new polymeric materials showing high tumor selectivity.
Two probable reasons why polymers with appropriate molecular weights show high tumor tissue selectivity are as follows:
The first one is that although a macromolecule such as a polymeric nano-particle can not permeate through the blood vessel walls in the normal tissues composed of regularly arrayed cells, it can permeate through the blood vessel walls in tumor tissues due to the coarse blood vessel walls of the tumor tissues as well as to the high vascular pressure in tumor tissues. The second one is that there is no lymphatic vessel as a discharge path for a biopolymer and polymer structure in tumor tissues. Therefore, in the tumor tissues, it is difficult for the polymer particles permeated therein to be discharged compared with in normal cells (R. Duncan, Parm. Sci. Technol. Today., 2, 441(1999)), and consequently, polymer particles permeated through the blood vessels wall are selectively accumulated in tumor tissues (H. Maeda, J. Fang, T. Inutsuka, Inter Immun 3, 319(2003)), yielding high selectivity of polymers to the tumor tissues.
The degree of such enhanced permeability and retention (EPR) effect of polymer particles closely depends on their residual times within blood and tissues. A polymer having a long blood circulation time can be regarded as a polymer having potential tumor tissue selectivity due to its enhanced permeability and retention effect. And it has been known that a long residual time of the polymer particles in tumor tissues is an essential condition for tumor tissue selectivity (E. Marecos, R. Weissleder, Bioconjugate Chem. 9, 184 (1998)). The above-described effects have been known only for some specific polymers, which illustrated from the recent clinical trials on human tumor tissues that such polymers can have high selectivity for tumor tissues, and therefore, can be applied to a selective antitumor agent.
Accordingly, many researches for the development of drug delivery systems using specific bio-affinitive polymer materials have been performed actively around the world (A. S. Lundberg and R. A. Weinberg, Eur, J, Cancer, 35, 531-539(1999)). A few examples of such attempts include SMANCS (neocarzinostatin bound to styrene-maleic anhydride copolymer) developed in Japan (K. Tsuchia, H. Maeda, Urology, 55, 495(2000)), and a conjugate of N-(2-hydroxy-propyl)methacrylamide (HPMA) and doxorubicin (P. A. Vasey, C. Twelves, Clin. Cancer Res., 5, 83 (1999)). The former SMANCS was recently approved in Japan, but are not widely used, and the latter has not been approved yet for clinical use. The main disadvantages of such conventional organic polymers are concerned with their biodegradability and low selectivity for tumor tissues.
Polyphosphazene is a new class of inorganic/organic hybrid polymer, which was first synthesized by Allcock Group in the United States (H. R. Allcock and R. L. Kugel, J. Am. Chem. Soc., 87, 4216(1965)). Polyphosphazene is a linear polymer in which its polymer backbone consists of phosphorus and nitrogen atoms alternately and organic substituents are linked to the phosphorus atoms as side groups, and exhibits a variety of different physical properties depending on the molecular structure of the side chains. Even though polyphosphazenes have good physical properties that organic polymers do not have, they could not have been widely used due to their expensiveness, and only used for limited purpose. In particular, polyphosphazenes could not be developed as drug delivery systems because of their high molecular weight (Mw>106 daltons) when prepared by the conventional method while polymers as a drug delivery material are required to have maximum molecular weight of 50,000-70,000 daltons for biocompatibility.
The present inventors discovered that the molecular weight of polyphosphazenes can be controlled by the amount of aluminum chloride used as a catalyst for the thermal polymerization reaction of the starting hexachlorocyclotriphosphazene (N3P3Cl6) to produce poly(dichlorophosphazene), (NPCl2)n (Youn Soo Sohn, et al., Macromolecules, 28, 7566 (1995)). Based on this discovery, the present inventors have performed researches for developing various new drug delivery materials. In particular, the present inventors recently discovered that water-solubility and biodegradability of polyphosphazenes can be controlled by introducing a hydrophilic poly(ethylene glycol) and a lipophilic amino acid into the polyphosphazene backbone by nucleophilic substitution of poly(dichlorophosphazene) (Youn Soo Sohn, et al. Macromolecules, 32, 2188 (1999)). The present inventors have also performed researches for applying the same for various purposes.